Editors' ChoiceImmunology

Keeping T Cells Quiet

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Science Signaling  30 Aug 2011:
Vol. 4, Issue 188, pp. ec239
DOI: 10.1126/scisignal.4188ec239

Naïve T cells depend on self-peptide–mediated activation of T cell receptors (TCRs) for survival, but how they are kept in a quiescent (unactivated) state despite TCR activation and whether this state is linked to their survival are unclear. Preventing the inappropriate activation of naïve T cells is important to maintaining a store of cells that are able to respond to foreign antigens (see commentary by Boothby and Lee). Noting that stimulation of the TCR activates the serine and threonine kinase mammalian target of rapamycin (mTOR), Yang et al. investigated mice whose T cells were deficient in the gene encoding the tumor suppressor protein Tsc1, which with Tsc2 forms a complex that inhibits mTOR complex 1 (mTORC1) activation. Thymocyte development was normal in Tsc1–/– mice; however, these mice had fewer peripheral T cells then did wild-type mice. When transferred to T cell–deficient mice, Tsc1–/– T cells showed poorer survival than did wild-type T cells. Tsc1–/– cells exhibited enhanced caspase activity compared with that in wild-type T cells, and TCR stimulation induced increased apoptotic cell death of Tsc1–/– cells relative to that of wild-type cells. Cell death in Tsc1–/– cells expressing the anti-apoptotic protein Bcl-2 was less than that in control Tsc1–/– T cells. Tsc1–/– T cells generated more reactive oxygen species (ROS) than did wild-type T cells, and treatment of Tsc1–/– mice with an antioxidant partially restored the number of peripheral T cells. Tsc1–/– T cells were larger than their wild-type counterparts, and a greater proportion of the Tsc1–/– cells were not quiescent but were undergoing cell cycling. Finally, Tsc1–/– mice had a weaker T cell–dependent immune response to bacterial infection than did wild-type mice. Together, these data suggest that Tsc1 is required to maintain naïve T cell quiescence.

K. Yang, G. Neale, D. R. Green, W. He, H. Chi, The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function. Nat. Immunol. 12, 888–897 (2011). [PubMed]

M. Boothby, K. Lee, A ‘Tsc, Tsc’ keeps the kids quie(scen)t and holds down ROS. Nat. Immunol. 12, 811–812 (2011). [PubMed]

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